The innate and adaptive immune systems play a fundamental role in combating microbial pathogens, as well as in targeting tumor cells. A critical component is presentation of foreign and self antigens for immune surveillance by the MHC family of cell surface glycoproteins. This proposal aims to characterize antigen loading and presentation by MHC and MHC-like molecules primarily through three-dimensional structure determination using x-ray crystallography. Our focus will be to elucidate: 1) Structural basis of lipid antigen presentation by the CD1 family to T cells through structure determination of CD1/antigen and CD1/TCR complexes. 2) Structural mechanism of antigen loading onto MHC class I by the membrane-bound peptide loading complex (PLC). A combined structural and biochemical approach using primarily high resolution x-ray crystallography will be used to characterize separate components and complexes of the peptide loading complex to identify important interactions within the PLC. These studies will provide structural models and functional insights into the exciting field of antigen loading, presentation, and restriction that will be useful in the design of novel therapeutics to combat microbial pathogens and cancer.